SUM M ARY Mantle cell lymphoma (MCL) is an aggressive B cell malignancy that is not yet curable. Ibrutinib was FDA- approved in 2013 to treat relapsed/refractory MCL; however, a second multi-center Phase II study led by our center revealed that no response or short-lived responses occur in 43% of patients. Furthermore, once patients progress on ibrutinib, the 1-year survival rate is only 22%; therefore, there is an urgent unmet need to overcome ibrutinib resistance and to study alternative treatment options. RNA sequencing and Ingenuity Pathway Analysis (IPA) of ibrutinib-sensitive and -resistant MCL clinical specimens suggested FoxM1 as a potential master regulator of ibrutinib resistance. FoxM1 is a transcription factor that is involved in numerous cellular processes such as proliferation, DNA damage response, senescence, and therapeutic resistance. Further analysis showed that FoxM1 is constitutively expressed in MCL, and interestingly, FoxM1 mRNA levels are higher in ibrutinib- resistant MCL cells compared with the ibrutinib-sensitive MCL cells, suggesting that targeting FoxM1 may produce anti-MCL effects in ibrutinib-resistant MCL cells. Indeed, FoxM1 inhibition with thiostrepton significantly reduced proliferation, arrested the cells, and induced apoptosis in ibrutinib-sensitive and -resistant MCL cells. Therefore, to address the contribution of FoxM1 activity to ibrutinib resistance and the effects of targeting FoxM1 to overcome ibrutinib resistance in relapsed/refractory MCL patients, we aim to 1) determine the functional role of FoxM1 in ibrutinib resistance by identifying FoxM1 targets in MCL using chromatin immunoprecipitation and DNA sequencing (ChIP-seq) and FoxM1 effectors by immunoprecipitation; 2) identify clinically viable inhibitors of FoxM1 or FoxM1-mediated pathways to overcome ibrutinib resistance in vitro and in vivo using patient-derived cancer models; and 3) and determine whether FoxM1 can be utilized as a clinical biomarker for MCL patient clinical outcomes and survival. Successful completion of the proposed study will provide strong evidence demonstrating the role of FoxM1 in ibrutinib resistance in MCL and that targeting FoxM1 overcomes ibrutinib resistance. This study will determine ibrutinib-resistant mechanisms and identify effective novel treatments to overcome ibrutinib resistance, ultimately leading to clinical strategies to treat relapsed/refractory ibrutinib-exposed MCL patients. .